Plague remains one of the most feared infectious diseases in humans. The etiological agent of the disease, Yersinia pestis, is disseminated by fleas and infects both humans and rodents. Y. pestis rapidly invades from the infection site into the lymphatic system and circulation, to produce the systemic and often fatal disease. Plague is endemic in many areas of the world, including the western United States. Globally about 2000 cases of plague are reported to the World Health Organization each year. Most of these cases are the bubonic form of the disease, usually a consequence of the transmission of bacteria to humans via bites from fleas that have previously fed on infected rodents. Although the most common mode of transmission is the flea bite, oral transmission can occur, often the result of an animal (polecat, weasel, ferret, cat) feeding on an infected mouse or other small rodent. Although less common, contact with domestic cats that have been exposed to Y. pestis is an important transmission mode because of the higher than average incidence of pneumonic plague that occurs in these cases. More rarely, cases of pneumonic plague are reported that are characterized by a short incubation period of 2 to 3 days and a high rate of mortality, even if treated. Pneumonic plague can be transmitted person-to-person or animal-to-person via the inhalation of contaminated air droplets. Pneumonic plague is the most likely form to be encountered if Y. pestis is used as a biological weapon.
Recent efforts to create a safe and effective pneumonic plague vaccine have focused on the development of recombinant subunit vaccines that elicit antibodies against two well characterized Y. pestis antigens, the F1 capsule and the virulence protein LcrV. In the past, live attenuated vaccine strains were generated by selection, rather than precise genetic manipulation, thus raising concern about their genetic composition and stability. An early live plague vaccine strain, EV76, has been used in some countries. However, EV76 has been known to cause disease in primates, raising questions about its suitability as a human vaccine. There is a need in the art, therefore, for a live plague vaccine using an adequately attenuated, rationally designed Y. pestis strain. This will provide the advantage of simultaneous priming against more than one antigen, thereby greatly enhancing the likelihood of broad-based protection.